An examination procedure known as ultrasonography or sonography is used clinically to delineate body structures by ultrasonic imaging. Progress and practical applications of diagnostic ultrasonic imaging have been delayed by lack of effective clinically usable contrast agents. This has especially been the situation for ultrasonic imaging of air-containing, externally-accessible body cavities, such as the gastrointestinal (GI) tract, uterus, and bladder.
Ultrasonic imaging utilizes an ultrasonic scanner to generate and receive sound waves. The scanner is placed on a body surface overlying the area to be imaged, and sound waves are directed toward that area. The scanner detects reflected sound waves and translates that data into images. When ultrasonic energy propagates through an inhomogeneous substance, the acoustic properties of the substance determine the degree of absorption, scattering, and transmission of the ultrasound. As ultrasound waves propagate through one medium to another, there is some degree of reflection at the interface. The degree of reflection is related to the acoustic properties of each material.
Contrast agents for diagnostic ultrasound were reviewed by Ophir and Parker, Ultrasound in Med. & Biol. (1989), 15:319-333. Various contrast agents were described for intravascular administration and imaging. These included free and encapsulated gas bubbles, colloidal suspensions, emulsions, and aqueous solutions. Mechanisms which can enhance image contrast are discussed, including backscatter contrast, attenuation contrast, and speed of sound contrast. The authors observed that the development of image-enhancing agents "has been slow and sporadic, and to date there are no completely satisfactory materials for clinical imaging." In a concluding paragraph, the authors added: "The clinical need for ultrasound contrast agents is high, but much interdisciplinary research, covering acoustic material properties, imaging, biochemistry, histology, toxicology and related specialties will be required before ultrasound contrast agents are commercially available and in routine clinical use."
With reference to encapsulated gas bubbles as ultrasonic imaging agents for intravascular administration, Ophir and Parker (1989), cited above, stated that feasibility remained uncertain because sufficiently stable bubbles of a size permitting administration in the peripheral circulation had not been developed. This was first accomplished by an invention of Dr. Steven B. Feinstein, as described in U.S. Pat. No. 4,774,958. By the sonication of an aqueous solution of human albumin, encapsulated microbubbles of relatively uniform size in the 2 to 5 micron range can be produced. The resulting imaging agent can pass through capillaries, and therefore can be administered in a peripheral vein for heart imaging, as reported by Keller, Feinstein, and Watson (1987), Amer. Heart J., 114:570-575. A concentrated shelf-stable microbubble imaging agent of this kind can be prepared as described in U.S. Pat. Nos. 4,844,880, and 4,957,656 assigned to Molecular Biosystems, Inc.
More recently, Molecular Biosystems has carried out research on imaging agents and methods for enhancing ultrasonic imaging of the gastrointestinal (GI) tract. This research was initially directed to particulate imaging agents, as described in U.S. Pat. No. 5,107,842, based on application Ser. No. 660,349, filed Feb. 22, 1991. Particulate ultrasonic imaging agents for the GI tract are also described in PCT Application WO 91/18612, published Dec. 12, 1991.
Heretofore, in development of ultrasonic contrast agents, principal emphasis has been directed to the contrast media containing dispersed air bubbles or solid particles, which reflect ultrasound and produce backscatter. These media function primarily as "positive" sonoreflective contrast agents, appearing light in the ultrasonic image rather than dark. Ultrasonic evaluation of body cavities is sometimes carried out in the absence of a positive contrast agent which, if present, would obscure the clarity of surrounding organ structures. However, even in the absence of a positive contrast agent, problems are encountered when there are substances within the body cavities which reflect sound. In order to overcome this problem, several authors have described the introduction of media into the body cavity through which the surrounding organs and tissues can be visualized. This method has achieved only limited success.
Weighall, et al. (1979), J. Clin. Ultrasound, 7:353-356, describe that "gastric air and peristalsis usually are obstacles to the ultrasound imaging of the tail of the pancreas"; and "air within the stomach drastically attenuates the transmission of ultrasound". The result is that "the stomach is a hinderance to ultrasound imaging of the organs of the left upper quadrant of the abdomen." In order to overcome this difficulty, the authors describe the use of intravenous glucagon to slow down peristalsis in conjunction with the ingestion of water to displace air. This method was not entirely satisfactory, since it did not result in the removal of all of the interfering microbubbles and food debris within the stomach which produced backscatter and appeared white in the ultrasonic images.
Warren, et al. (1978) J. Clin. Ultrasound, 6:315-320, describes the formation of an "ultrasonic window" by using a liquid-filled stomach. A mucilaginous suspension of methylcellulose was administered in conjunction with an intravenous injection of Buscopan to slow peristalsis. The authors report that the suspension "allows good through-transmission of sound", but the photographs presented in the article demonstrate that the clumped methylcellulose mucilages appear as white granular sonoreflective bodies (positive contrast) in the ultrasonic images. The presence of the mucilages would thus limit the usefulness of this procedure for ultrasonic imaging of the upper abdomen.
For sonographic examination of childrens' stomachs, Stringer et al. (1986), J. Ultrasound Med., 5:183-188, used water with added glucose.
Worlicek et al. (1989), J. Clin. Ultrasound, 17:5-14, describes the ultrasonic imaging of the gastrointestinal tract after having the patient ingest a significant quantity of orange juice in conjunction with an intravenous injection of Buscopan . The success of this procedure depends largely on the positioning of the patient during the examination due to the presence of air in the gastrointestinal tract. The authors describe that "the air, which completely reflects ultrasonic waves, is removed from the section of the stomach under investigation by appropriate positioning."
Current progress in transabdominal ultrasonography of the stomach and duodenum was reviewed by Op den Orth, Curr. Opin. Radiol. (1990), 2:394-399. Published research was summarized on the examination of the stomach wall with the aid of fluid media. In the conclusion, the authors note that a tilting table is essential for patient positioning during the ultrasonic examination. They also note that, "Even with this type of table, however, the fundus is sometimes difficult to examine."
There thus exists a need for a contrast agent which permits through-transmission of ultrasound with negligible reflection or back-scatter, and therefore appears black in contrast to the whiter appearing surrounding tissue, i.e., a "negative" contrast agent. Such a contrast agent which facilitates the removal of gas in the body cavities is necessary for clinically successful ultrasonic examination of the body cavity tissues and surrounding organs which may be hampered by the presence of echogenic substances.